(1) Field of the Invention
This invention relates to novel inosadiamine derivatives useful as antitumor agents.
(2) Description of the Prior Art
Cancer is now the second leading cause of death in the United States and it is believed that the proportion of deaths due to cancer will climb in coming years throughout the world due to such factors as the increase in the average life span, the large number of persons completing 20-30 years as active smokers, environmental carcinogens and the more widespread use of various preservatives in foods and other substances which are ingested. The trend in cancer therapy is now in the direction of earlier and more universal use of chemotherapy alone or in conjunction with radiation and surgery, in contrast to previous use of chemotherapy as a last resort in surgically inoperative cases.
Various nitrosourea compounds have been disclosed in the literature as active therapeutic agents for the treatment of experimental and clinical neoplasms. The three members of this class which have been clinically studied are BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], CCNU [1-(2-chloroethy)-3-cyclohexyl-1-nitrosourea] and methyl CCNU [1-(2-chloroethyl)-2-(4-methylcyclohexyl)-1-nitrosourea]. These compounds have been shown to have activity either alone or in combination with other agents against primary brain tumors, malignant melanoma, lymphomas and a few selected solid tumors.
Montgomery et al. have disclosed in J. Med. Chem., 18(1), 104 (1975) the preparation of a streptozotocin analog of the formula ##STR2## in which a 2-chloroethyl group was substituted for the methyl group of the N-nitrosourea moiety in streptozotocin. The new analog named chlorozotocin is reported to possess enhanced effectiveness against leukemia L1210 relative to streptozotocin.
The inosadiamine derivative of the formula ##STR3## was disclosed by Suami et al. in Bull. Chem. Soc. Japan, 43(9), 2953 (1970) as being active against Ehrlich ascites tumor and Hela carcinoma.
Suami et al. have also reported preparation of the compound of the formula ##STR4## in Bull. Chem. Soc. Japan, 48 (12), 3763 (1975). The above compound is said to have activity against L1210 leukemia in mice. Other inosamine nitrosoureas are disclosed in Belgian Pat. No. 832,227 and Japanese Patent Publication J51-52160 (Derwent No. 47028X/25).